Dietz Matthew, Gates Travis J, Sikdar Rakesh, Subramanian Subbaya, Elias Mikael H, Staley Christopher
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA.
BioTechnology Institute, University of Minnesota, St. Paul, Minnesota, USA.
Cancer Med. 2025 Jun;14(12):e71009. doi: 10.1002/cam4.71009.
The gut microbiota is associated with colorectal cancer (CRC) risk and CRC metastatic potential. However, the role of bacteria in CRC progression and metastasis remains unclear.
Here, we hypothesized that microbial communication, mediated through quorum sensing (QS), was a critical component regulating microbial functions related to cancer progression and metastasis.
MATERIALS & METHODS: To test this, male and female C57BL/6 mice were injected with organoids modeling aggressive colon cancer (CRC), carrying mutations in Apc, Kras, p53, and Smad4. Two groups of mice were treated with two different quorum quenching (QQ) lactonases (GcL or SsoPox) for 8 weeks (n = 10/group/sex). Fecal samples were collected weekly and characterized by Illumina next-generation sequencing, with tissues collected during necropsy.
Male mice treated with SsoPox had fewer metastases than control mice (χ = 3.206, p = 0.073), with no SsoPox-treated male developing a metastasis. In contrast, female mice treated with SsoPox had more metastases than control mice (χ = 2.554, p = 0.110), and every female, SsoPox-treated mouse that developed a primary tumor also developed metastasis by the experimental endpoint. However, QQ treatment was shown to minimally affect the gut microbiome composition. Similarly, no significant differences were observed in inflammatory response as assessed by immunofluorescent staining or fecal concentrations of immunoglobulin A, calprotectin, or lipocalin-2. Differences in fecal short-chain fatty acid concentrations also did not differ significantly.
These results suggest that QQ treatment has a sex-based effect on CRC metastatic rate.
Targeting communication among the gut microbiome may be a promising avenue for the development of CRC therapies that minimally impact microbial community composition and host immune response.
肠道微生物群与结直肠癌（CRC）风险及CRC转移潜能相关。然而，细菌在CRC进展和转移中的作用仍不明确。
在此，我们假设通过群体感应（QS）介导的微生物通讯是调节与癌症进展和转移相关的微生物功能的关键组成部分。
为验证此假设，给雄性和雌性C57BL/6小鼠注射模拟侵袭性结肠癌（CRC）的类器官，这些类器官携带Apc、Kras、p53和Smad4基因的突变。两组小鼠分别用两种不同的群体猝灭（QQ）内酯酶（GcL或SsoPox）处理8周（每组/性别n = 10）。每周收集粪便样本，通过Illumina下一代测序进行表征，并在尸检时收集组织。
用SsoPox处理的雄性小鼠转移灶比对照小鼠少（χ = 3.206，p = 0.073），没有接受SsoPox处理的雄性小鼠发生转移。相比之下，用SsoPox处理的雌性小鼠转移灶比对照小鼠多（χ = 2.554，p = 0.110），并且到实验终点时，每只接受SsoPox处理且发生原发性肿瘤的雌性小鼠也都发生了转移。然而，QQ处理对肠道微生物群组成的影响极小。同样，通过免疫荧光染色或粪便中免疫球蛋白A、钙卫蛋白或脂质运载蛋白-2浓度评估的炎症反应也未观察到显著差异。粪便短链脂肪酸浓度的差异也无显著不同。
这些结果表明QQ处理对CRC转移率有基于性别的影响。
针对肠道微生物群之间的通讯进行干预可能是开发对微生物群落组成和宿主免疫反应影响极小的CRC治疗方法的一个有前景的途径。
